"Baroreflex" Failure" A Rare Late Effect Of Radiation Treatment

I came across this article written by a Gentleman on another forum about late-term post-radiation effects which can give you a condition where your blood pressure swings wildly from high to low or low to high without notice. There is no cure but some control can be realized with meds. I just wanted to let the group know about this and make people aware. In fact, there may be someone on here that has this problem but I have never seen it brought up that I can remember. Below I will post his description and then some information below it. Radiation for head and neck cancers can cause debilitation problems years after treatment is completed. I felt this was important enough to share with our group. Be aware this can easily be a life-or-death issue.

Take Care, God Bless-Russ

The fellow that made the original posting goes by the name of Criswell and here is his post and then information on this post-radiation situation follows.

Criswell

Mar 7, 2020 • 11:45 AM

I had radiation and chemo for tongue cancer in 2013-2014. While I am now cancer-free in 2020 I am suffering from Baroreflex Failure, a rare late effect of radiation treatment. Basically, it means that all control of my blood pressure is now gone forever. My systolic readings can range from 65 to 235 for no reason, all within an hour. There is no treatment, but some management can be achieved through medication. I can't find anyone else who has been through what I am experiencing. I am now a ticking time bomb, in fear of my life even while being cancer-free. I would love to hear from someone in my situation.

Information on this condition--

BARORECEPTOR DYSFUNCTION

Radiation for head and neck cancers can cause debilitation problems years after treatment is completed. When radiated areas include the neck or base of the skull, as is the case with tonsil and base of tongue primaries, the long-term damage may not surface for several years. Much of the damage is caused by radiation-induced fibrosis as the body continually attempts to heal the tissue damaged during treatment. We have pairs of nerves that extend from the brain through the neck and they are responsible for most functions of the body, as well as significant pain as fibrosis sets in. These nerves are called Cranial Nerves and the Lower Cranial Nerves are the nerves that are most affected from radiation-induced fibrosis. The particular Lower Cranial Nerves related to heart rate and blood pressure that are affected are the Glossopharyngeal Nerve (Cranial Nerve IX) and the Vagus Nerve (Cranial Nerve X). The Glossopharyngeal Nerve contains motor fibers, for activating muscles, and sensory nerve fibers to transmit information to the brain, via afferent nerve fibers, and receive instructions from the brain, via efferent nerve fibers. To regulate blood pressure, the glossopharyngeal nerve receives information from visceral fibers that sense oxygen levels in the trunk and the carotid bodies for measuring blood pressure. This information is sent to the brain to allow the autonomic nervous system (automatic body functions in simple terms) to control oxygen adjustment and blood pressure, for example. The Vagus Nerve is perhaps the most important nerve in the body and is also called the meandering or wandering nerve. To regulate blood pressure and heart rate, sensory nerve fibers of the vagus nerve receive information, via afferent nerve fibers from the carotid and aortic bodies. The vagus nerve, via efferent nerve fibers then innervates the heart and lungs. Baroreceptor Function, or baroreflex is a term that describes fluctuations in heart rate and blood pressure to maintain blood pressure as constant as possible. Baroreflex, the reflex mechanism by which baroreceptors regulate blood pressure, includes the transmission of nerve impulses from the baroreceptors to a specific portion of the brain called the Medulla Oblongata or Command Center of the body, specifically the medulla nucleus tractus solitaries (NTS) in response to a change in blood pressure that produces vasodilation (opening up of blood vessels) and a decrease in heart rate when blood pressure increases and vasoconstriction (closing of blood vessels) and an increase in heart rate when blood pressure decreases. Baroreflex can affect the heart and the brain by insufficient or excessive blood pressure, or changes in oxygen levels in the blood supplying the brain. Baroreceptor Failure is a condition that means the process is out of control while Baroreceptor Dysfunction more accurately describes what many people that have had radiation treatment and/or surgery to the neck as treatment for head and neck cancer can develop because baroreflex is sporadic and in control some of the time. Baroreceptor Dysfunction is a chronic disorder, occurring about 6 years after the completion of treatment in some cases. (1,2)

Baroreceptors are mechano-sensitive terminals of the glossopharyngeal (Cranial Nerve IX) and the vagus (Cranial Nerve X) nerves that project to the nucleus tractus solitarius (NTS) in the caudal medulla located in the medulla oblongata. The sinus nerve branches off of the glossopharyngeal nerve to the interior carotid artery to dilate or constrict the carotid artery flow to the brain. In response to postural changes, efferent projections from the NTS to sympathetic and parasympathetic preganglionic neurons in the brain and spinal cord govern acute fluctuations in heart rate and blood pressure. Baroreceptors are found in the blood vessels of all vertebrate animals, residing in the heart, vena cavae, arteries, carotid sinuses, and the aortic arch. The process is continuous and necessary to ensure blood pressure is maintained. The most sensitive baroreceptors are located in the carotid sinuses, usually in the field of radiation, and the aortic arch, the second major anatomical region of the aorta that sends blood from the left ventricle of the heart to the rest of the body. Impaired afferent signaling of this arterial baroreceptor reflex arc in humans causes a sustained increase in mean

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arterial pressure lability (constant change), often leading to both paroxysms (sudden change) of hypercatecholaminergic tone (excitement of neurotransmitters) that resemble pheochromocytoma (attacks of raised blood pressure, heart palpitations, and headache) and contrasting episodes of profound orthostatic hypotension (decrease in systolic blood pressure of 20 mm Hg or a decrease in diastolic blood pressure of 10 mm Hg within three minutes of standing when compared with blood pressure from the sitting or supine position). What causes fluctuations in blood pressure? Cardiovascular adaptations are regulated by the autonomic nervous system. Standing activates afferent autonomic neural pathways to induce baroreceptor unloading, causing increases in efferent sympathetic outflow and vasoconstriction, to increase venous return and maintain resting blood pressure. When we change from sitting to standing, information is sent via baroreceptors to the brain because there is an automatic increase in systolic blood pressure. Orthostatic venous pooling (excess blood and fluid pooling from poor blood return to the heart) occurs in the legs when we stand and our body needs to modulate the blood pressure. Baroreflex failure occurs when afferent baroreceptor nerves or their central connections are impaired, causing a loss of buffering, and wide fluctuations of blood pressure and heart rate. Impairment of the baroreflex may present under a wide spectrum of symptoms with hypertensive crisis as the most common. Over a period of time, volatile hypertension (high blood pressure) with periods of hypotension (low blood pressure) occurs and may continue for months and years, usually with some attenuation of pressor surges and greater prominence of depressor valleys. Other scenarios include orthostatic tachycardia (rapid heartbeat) or orthostatic intolerance may appear, or vagotonia (excessive excitability of the vagus nerve resulting typically in vasomotor instability, constipation, and sweating) with severe bradycardia (low heartbeat) and hypotension and episodes of sinus arrest (loss of electrical signal to the heart that allows the heart to contract). In particular, after neck irradiation, long-term injury occurs commonly in the carotid arteries. Atherosclerotic (thickening or hardening of the walls of arteries) and thrombotic complications (blood clots or dislodged plaque in arteries that can result in heart attack or stroke) have drawn the most attention. Among 910 patients who survived at least 5 years after irradiation of head and neck tumors, stroke occurred in 6% and clinically significant carotid stenosis in 17%. Chronic inflammation and fibrosis of carotid arterial walls might lead to “splinting” of carotid sinus baroreceptors. Because these are stretch or distortion receptors, stiffening of the carotid sinus would be expected to lead to a decreased gain of the arterial baroreflex. Nevertheless, few reports have noted baroreflex failure after neck or brain stem surgery or irradiation. (4) At the American Neurological Association 133rd Annual Meeting, investigators presented a retrospective review highlighting the clinical features and typical findings on autonomic testing in patients with radiation-induced baroreflex failure. "The important thing is to recognize that patients who've had head and neck radiation may have late complications that may not manifest for years after treatment," second author Sara Schrader, MD, from the Mayo Clinic in Scottsdale, Arizona, told Medscape Neurology & Neurosurgery. "Radiation can cause multiple cranial neuropathy, which can manifest in many ways," Dr. Schrader noted. (5)

Neck Radiation Associated With Cranial Neuropathy

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The researchers were led by Brent Goodman, MD, also from the Mayo Clinic. They identified 34 patients who had a history of neck radiation, labile hypertension, orthostatic hypotension, or syncope. The malignancy type was squamous-cell carcinoma in all but 2 patients. The mean age of participants at the time of diagnosis was 63 years. The average time from radiation exposure to the development of symptoms was 6.4 years. Radiation doses ranged from 55 Gy to 70 Gy. Formal autonomic testing was performed in 22 patients. Cardiovascular adrenergic function was the most frequent abnormality, showing impairment in late phase 2 and 4 during the Valsalva maneuver.

Neurological Complications Following Neck Radiation

Signs Symptoms Patients (%) Autonomic Postural lightheadedness 97 Labile hypertension 78 Syncope 73 Cardiac dysrhythmia 9 Bulbar Dysphagia 78 Dysarthria 33 Cerebrovascular Stroke 12 Carotid artery stenosis/occlusion 57 Vertebral artery stenosis 7

"This is a retrospective study, and some of the patients we've seen clinically, but the vast majority, we have not," Dr. Schrader pointed out during an interview. "The data we have for patients were not uniform, and testing may have differed," she noted. Shapiro and colleagues discovered lightheadedness and fluctuations in cardiovascular reflexes attributable to baroreceptor damage caused by radiation was elusive on routine cardiovascular testing. In a broader sense, cardiovascular dysautonomia has been linked to carotid sinus dysfunction occurring from radiation damage but also included bilateral carotid artery stenosis as a potential etiology. Further, response to traditional management when autonomic failure is caused by centrally mediated dysfunction is not effective, leading to severely diminished quality of life with greater risk for cardiovascular morbidity and mortality. (6) Table 1 presents an excerpt of head and neck cancer patients that received radiation or patients that had carotid stenosis.

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Table 1. Excerpts of Characteristics of Head and Neck Radiation and Carotid Stenosis Patient Cases With Orthostatic Hypotension and Supine Hypertension Related to Baroreceptor Dysfunction

Case

Age, y Sex

FollowUp, mo

Cause of Baroreceptor Dysfunction

Pharmacologic Interventions

Nonpharmacologic ic Interventions

αAgonists

Fludrocortis one

Mean Home BPs/HR at Baseline (Supine/Standin g)

Mean Home BPs/HR at Last Visit (Supine/Standin g)

1. Abbreviations: BID, twice a day; BP, blood pressure; F, female; HR, heart rate; M, male.

2. Nonpharmacological interventions include: moderate sodium intake (2500-5000 mg/d), predominantly before noon on a given day, use of support stocking to thighs (25-30 mmHg), and when needed sleeping with head/neck elevated to 15-20 degree angle.

Case 1 84 M 1

Neck radiation therapy for laryngeal cancer and advanced bilateral carotid stenosis

Atenolol 25 mg BID and isradipine 5 mg at bedtime + – −

167/67/65 145/65/60

94/62/61 117/55/58

Case 3 63 M 14

Neck radiation therapy for tongue cancer

Atenolol 25 mg BID and isradipine 5 mg at bedtime + – −

146/91//57 136/86/58

97/63/60 104/84/62

Case 4 74 F 12

Advanced bilateral carotid stenosis

Atenolol 100 mg at night and nicardipine 40 mg at bedtime and 20 mg in the am + – −

162/90/77 155/85/70

110/76/75 147/70/70

Case 5 84 M 1

Advanced bilateral carotid stenosis

Atenolol 100 mg at night and nicardipine 40 mg at bedtime − – −

180/80/75 160/92/68

80/50/80 120/70/67

Case 6 82 M 12

Neck radiation therapy for head and neck cancer None +

Midodrine 5 mg in am as needed −

130/68/62 122/66/60

86/58/64 104/60/61

Case 7 63 M 12

Neck radiation therapy for tongue cancer

Atenolol 50 mg at bedtime + – +

185/105/62 152/82/58

155/76/68 146/80/60

Case 10 65 M 36

Neck radiation therapy for head and neck cancer

Atenolol 50 mg at bedtime and guanfacine 2 mg at bedtime + – −

156/80/84 145/77/56

128/60/82 123/67/60

Case 11 50 M 1

Neck radiation therapy for head and neck cancer

Nebivolol 10 mg qam and 5 mg qpm with ramipril 5 mg BID + – +

136/86/85 128/80/80

110/75/95 118/75/87

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Autonomic dysfunction leads to impairment of compensatory mechanisms and clinically results in orthostatic hypotension, defined as a reduction in SBP ≥20 mm Hg or diastolic BP ≥10 mm Hg within 3 minutes of standing or head-up tilt to an angle of at least 60°. In hypertensive patients, a reduction of SBP >30 mm Hg is more appropriate. In addition to unpleasant and disabling symptoms, orthostatic hypotension is associated with an increased risk of falls, cognitive dysfunction, (7) coronary arterial disease, (8) chronic kidney disease, (9) stroke, (10) and cardiovascular and all-cause mortality. (11,12) The mechanisms behind them are unclear, and whether orthostatic hypotension is a cause or consequence of comorbidities is still uncertain. Orthostatic hypotension is associated with nondipping or reverse-dipping pattern of diurnal BP, while the cardiovascular risk remained even after adjustment for such diurnal BP patterns. (13) Once orthostatic hypotension is diagnosed, clinicians should take the patient's medical history and physical examination carefully. Certain medications such as antihypertensive drugs (eg, α-blockers, diuretics, and vasodilators) and antidepressants, and changes of daily life (eg, dehydration, weight loss, diet, infection, stress, sleep problems) are common causes of orthostatic hypotension. Assessments of other manifestations of autonomic neuropathy or neurodegenerative diseases can be helpful in the diagnosis of neurogenic orthostatic hypotension. Laboratory tests such as anemia, glucose, electrolyte, renal function, hormones (eg, thyroid and adrenal), and proteinuria might be helpful. Nonpharmacologic measures are important components of therapy of orthostatic hypotension. These include removal of offending medications, patient education to avoid precipitating factors, physical and dietary interventions, and patient education. Recognition and removal of drugs, which can cause orthostatic hypotension, is crucial. The most common offending medications are diuretics, α-adrenergic antagonists, and antidepressants.

Patients should also be instructed to 1. maintain appropriate hydration throughout the day by drinking at least 1.5 L/d to 2 L/d of water during meals and before exercise and also rapid intake of water in the morning before getting out of bed; 2. arise slowly, in stages, from supine to sitting to standing, particularly in the morning when orthostatic hypotension is more pronounced; 3. avoid activities that reduce venous return such as walking in hot weather, or straining; 4. elevate the head of the bed 10° to 20° to decrease nocturnal diuresis and maintain intravascular volume; 5. prevent episodes of postprandial hypotension by avoiding large meals, minimizing alcohol intake, and avoiding standing immediately after eating; and 6. perform leg-crossing maneuvers while actively standing to increase cardiac output and systemic BP. (14) The use of compression stockings that produce at least 20- to 25-mm Hg pressure or tight abdominal binders permits the application of graded pressure to the lower extremities and lower abdomen, thereby minimizing

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peripheral blood pooling in lower extremity and splanchnic circulation. It is essential that such stockings extend above the knees to the waist since most peripheral pooling occurs in the splanchnic circulation. Many patients, particularly those with peripheral neuropathies or those living in hot climates, poorly tolerate compression stockings. The efficacy of compression stockings and abdominal binders was validated in a small crossover study that showed reduced orthostatic BP decrease and symptoms compared with controls. (15) Increased salt and water intake are essential parts of treatment. Rapid ingestion of 500 cc of water in <5 minutes can serve as a therapeutic measure in symptomatic patients. The BP effect is observed in the first 5 to 10 minutes and peaks around 30 minutes after ingestion and is mediated by a sympathetic reflex rather than a volume effect. (16) Patients should be instructed to consume high-sodium–containing foods. Salt tablets may also be prescribed. While the optimal dose will vary among patients, a target dose of 6 g/d to 10 g/d of sodium taken with breakfast and lunch, or a target urinary sodium level of 150 mEq to 200 mEq should be maintained. Night dosing of salt intake should be minimized to avoid worsening of supine hypertension. (17)